Coronary Artery Disease and Myocardial Infarction
The major complications of Coronary Artery Disease, i.e. Myocardial infarction (MI) and Acute Coronary Syndrome (ACS), are the leading causes of hospital admissions in industrialized countries. Cardiovascular disease continues to be the principle cause of death in the United States, Europe and Japan. The costs of the disease are high both in terms of morbidity and mortality, as well as in terms of the financial burden on health care systems.
Myocardial infarction generally occurs when there is an abrupt decrease in coronary blood flow following a thrombotic occlusion of a coronary artery previously damaged by atherosclerosis (i.e. in subjects with coronary artery disease). In most cases, infarction occurs when an atherosclerotic plaque fissures, ruptures or ulcerates and when conditions favor thrombogenesis. In rare cases, infarction may be due to coronary artery occlusion caused by coronary emboli, congenital abnormalities, coronary spasm, and a wide variety of systemic, particularly inflammatory diseases. Medical risk factors for MI include cigarette smoking, diabetes, hypertension and serum total cholesterol levels >200 mg/dL, elevated serum LDL cholesterol, and low serum HDL cholesterol. Event rates in individuals without a prior history of cardiovascular disease are about 1%. In individuals who have had a first MI or ACS, the risk of a repeat MI within the next year is 10-14%, despite maximal medical management including angioplasty and stent placement.
Atherosclerosis can affect vascular beds in many large and medium arteries. Myocardial infarction and unstable angina (acute coronary syndrome (ACS)) stem from coronary artery atherosclerosis (Coronary Artery Disease), while ischemic stroke most frequently is a consequence of carotid or cerebral artery atherosclerosis. Limb ischemia caused by peripheral arterial occlusive disease (PAOD) may occur as a consequence of iliac, femoral and popliteal artery atherosclerosis. The atherosclerotic diseases remain common despite the wide-spread use of medications that inhibit thrombosis (aspirin) or treat medical risk factors such as elevated cholesterol levels in blood (statins), diabetes, or hypertension (diuretics and anti-hypertensives).
Atherosclerotic disease is initiated by the accumulation of lipids within the artery wall, and in particular, the accumulation of low-density lipoprotein (LDL) cholesterol. The trapped LDL becomes oxidized and internalized by macrophages. This causes the formation of atherosclerotic lesions containing accumulations of cholesterol-engorged macrophages, referred to as “foam cells”. As disease progresses, smooth muscle cells proliferate and grow into the artery wall forming a “fibrous cap” of extracellular matrix enclosing a lipid-rich, necrotic core. Present in the arterial walls of most people throughout their lifetimes, fibrous atherosclerotic plaques are relatively stable. Such fibrous lesions cause extensive remodeling of the arterial wall, outwardly displacing the external, elastic membrane, without reduction in luminal diameter or serious impact on delivery of oxygen to the heart. Accordingly, patients can develop large, fibrous atherosclerotic lesions without luminal narrowing until late in the disease process. However, the coronary arterial lumen can become gradually narrowed over time and in some cases compromise blood flow to the heart, especially under high demand states such as exercise. This can result in reversible ischemia causing chest pain relieved by rest called stable angina.
In contrast to the relative stability of fibrous atherosclerotic lesions, the culprit lesions associated with myocardial infarction and unstable angina (each of which are part of the acute coronary syndrome) are characterized by a thin fibrous cap, a large lipid core, and infiltration of inflammatory cells such as T-lymphocytes and monocyte/macrophages. Non-invasive imaging techniques have shown that most MI's occur at sites with low-or intermediate-grade stenoses, indicating that coronary artery occlusion is due most frequently to rupture of culprit lesions with consequent formation of a thrombus or blood clot and not solely due to luminal narrowing by stenosis. Plaque rupture may be due to erosion or uneven thinning of the fibrous cap, usually at the margins of the lesion where macrophages enter, accumulate, and become activated by a local inflammatory process. Thinning of the fibrous cap may result from degradation of the extracellular matrix by proteases released from activated macrophages. These changes producing plaque instability and risk of MI may be augmented by production of tissue-factor procoagulant and other factors increasing the likelihood of thrombosis.
In acute coronary syndrome, the culprit lesion showing rupture or erosion with local thrombosis typically is treated by angioplasty or by balloon dilation and placement of a stent to maintain luminal patency. Patients experiencing ACS are at high risk for a second coronary event due to the multi-vessel nature of coronary artery disease with event rates approaching 10-14% within 12 months after the first incident.
The emerging view of MI is as an inflammatory disease of the arterial vessel wall on preexisting chronic atherosclerotic lesions, sometimes triggering rupture of culprit lesions and leading to local thrombosis and subsequent myocardial infarction. The process that triggers and sustains arterial wall inflammation leading to plaque instability is unknown, however, it results in the release into the circulation of tumor necrosis factor alpha and interleukin-6. These and other cytokines or biological mediators released from the damaged vessel wall stimulate an inflammatory response in the liver causing elevation in several non-specific general inflammatory markers including C-reactive protein. Although not specific to atherosclerosis, elevated C-reactive protein (CRP) and serum amyloid A appear to predict risk for MI, perhaps as surrogates for vessel wall inflammation. Many general inflammatory markers predict risk of coronary heart disease, although these markers are not specific to atherosclerosis. For example, Stein (Stein, S., Am J Cardiol, 87 (suppl):21A-26A (2001)) discusses the use of any one of the following serum inflammatory markers as surrogates for predicting risk of coronary heart disease including C-reactive protein (CRP), serum amyloid A, fibrinogen, interleukin-6, tissue necrosis factor-alpha, soluble vascular cell adhesion molecules (sVCAM), soluble intervascular adhesion molecules (sICAM), E-selectin, matrix metalloprotease type-1, matrix metalloprotease type-2, matrix metalloprotease type-3, and matrix metalloprotease type-9. Elevation in one more of these serum inflammatory markers is not specific to coronary heart disease but also occurs with age or in association with cerebrovascular disease, peripheral vascular disease, non-insulin dependent diabetes, osteoarthritis, bacterial infection, and sepsis.
Elevated CRP or other serum inflammatory markers is also prognostic for increased risk of a second myocardial infarct in patients with a previous myocardial infarct (Retterstol, L. et al., Atheroscler., 160: 433-440 (2002)).
Although classical risk factors such as smoking, hyperlipidemia, hypertension, and diabetes are associated with many cases of coronary heart disease (CHD) and MI, many patients do not have involvement of these risk factors. In fact, many patients who exhibit one or more of these risk factors do not develop MI. Family history has long been recognized as one of the major risk factors. Although some of the familial clustering of MI reflects the genetic contribution to the other conventional risk factors, a large number of studies have suggested that there are significant genetic susceptibility factors, beyond those of the known risk factors (Friedlander Y, et al., Br. Heart J. 1985; 53:382-7, Shea S. et al., J. Am. Coll. Cardiol. 1984; 4:793-801, and Hopkins P. N., et al., Am. J. Cardiol. 1988; 62:703-7). Major genetic susceptibility factors have only been identified for the rare Mendelian forms of hyperlipidemia such as a familial hypercholesterolemia.
Genetic risk is conferred by subtle differences in genes among individuals in a population. Genes differ between individuals most frequently due to single nucleotide polymorphisms (SNP), although other variations are also important. SNP are located on average every 1000 base pairs in the human genome. Accordingly, a typical human gene containing 250,000 base pairs may contain 250 different SNP. Only a minor number of SNPs are located in exons and alter the amino acid sequence of the protein encoded by the gene. Most SNPs may have little or no effect on gene function, while others may alter transcription, splicing, translation, or stability of the mRNA encoded by the gene. Additional genetic polymorphism in the human genome is caused by insertion, deletion, translocation, or inversion of either short or long stretches of DNA. Genetic polymorphisms conferring disease risk may therefore directly alter the amino acid sequence of proteins, may increase the amount of protein produced from the gene, or may decrease the amount of protein produced by the gene.
As genetic polymorphisms conferring risk of disease are uncovered, genetic testing for such risk factors is becoming important for clinical medicine. Examples are apolipoprotein E testing to identify genetic carriers of the apoE4 polymorphism in dementia patients for the differential diagnosis of Alzheimer's disease, and of Factor V Leiden testing for predisposition to deep venous thrombosis. More importantly, in the treatment of cancer, diagnosis of genetic variants in tumor cells is used for the selection of the most appropriate treatment regime for the individual patient. In breast cancer, genetic variation in estrogen receptor expression or heregulin type 2 (Her2) receptor tyrosine kinase expression determine if anti-estrogenic drugs (tamoxifen) or anti-Her2 antibody (Herceptin) will be incorporated into the treatment plan. In chronic myeloid leukemia (CML) diagnosis of the Philadelphia chromosome genetic translocation fusing the genes encoding the Bcr and Abl receptor tyrosine kinases indicates that Gleevec (STI571), a specific inhibitor of the Bcr-Abl kinase should be used for treatment of the cancer. For CML patients with such a genetic alteration, inhibition of the Bcr-Abl kinase leads to rapid elimination of the tumor cells and remission from leukemia.
Restenosis
Coronary balloon angioplasty was introduced in the late 1970s as a less invasive method for revascularization of coronary artery disease patients than the coronary artery bypass graft (CABG) surgeries. Since then there has been a quick progress in the development of new percutaneous devices to revascularize areas with limited blood flow. However, the expanded use of angioplasty has shown that the arteries react to angioplasty by a proliferative process that limits the success of this treatment. This process is known as restenosis.
Restenosis is defined as a re-narrowing of the treated segment, which equals or exceeds 50% of the lumen in the adjacent normal segment of the artery. Depending on the patient population studied, the restenosis rates range from 30% to 44% of lesions treated by balloon dilation. This problem prompted a search for interventional techniques that minimizes the risk of restenosis. Several clinical trials have shown a significant reduction in the restenosis rates with endovascular stenting. The purpose of stenting is to maintain the arterial lumen by a scaffolding process that provides radial support. Stents, usually made of stainless steel, are placed in the artery either by a self-expanding mechanism or, using balloon expansion. However, in-stent restenosis still remains a major problem in the field of percutaneous, transluminal coronary angioplasty (PTCA), requiring patients to undergo repeated procedures and surgery. Restenosis is the result of the formation of neointima, a composition of smooth muscle-like cells in a collagen matrix. The current treatment modalities for in-stent restenosis include repeat balloon angioplasty, repeat stenting, cutting balloon angioplasty, directional coronary atherectomy, rotational coronary atherectomy, brachytherapy, and drug-eluting stents (DES). The restenosis problem can be minimised by local intravascular irradiation (intracoronary brachytherapy) and by the introduction of DES and these treatments have been shown to successfully preventing cell proliferation after stent implantation or angioplasty.
Intracoronary brachytherapy is a treatment in which sealed sources of radioactive material are used to deliver radiation at a very short distance by placing them in the artery lumen at the site of the atherosclerotic lesion. The physical benefit of brachytherapy is that doses of radiation can be delivered almost directly to the target with a very rapid falloff of dose to the surrounding normal tissue. The rationale underlining this modality is based on the ability of ionizing radiation to inhibit cell proliferation, in this case, the proliferation of smooth muscle cells that tend to form a neointima. In the near future, it would be important to be able to classify patients with respect to the risk of having in-stent restenosis. This classification can potentially be made on the basis of genetic risk factors. The outcome of the classification may determine which therapy is most appropriate and also where coronary bypass surgery has to be considered.
Aneurysms
Degenerative changes of the arterial wall may cause localized dilatation, or aneurysm, of the artery, including abdominal aorta aneurysm (AAA) and intracranial aneurysm (IA). Atherosclerotic changes of the vessel wall are found in the majority of AAA that are characterized histopathologically by chronic inflammation, destructive remodelling of elastic media and depletion of medial smooth muscle cells resulting in marked weakening of the aortic wall. In contrast, berry aneurysms of intracranial arteries are not associated with atherosclerosis. Furthermore, the histopathological features of IA are different. The typical berry aneurysms of intracranial arteries, located at arterial bifurcations, have a thin, or no, media and the internal elastic lamina is either absent or severely fragmented.
Both AAA and IA represent a degenerative process of the arteries leading to their enlargement that is usually asymptomatic with natural history culminating in either a therapeutic intervention or rupture. Rupture of IA leads to subarachnoid haemorrhage, and rupture of both IA and AAA have high morbidity and mortality. In the case of AAA the rupture risk increases with the growth rate as well as the size of the aneurysm.
Intracranial aneurysm (IA), also called cerebral aneurysm or brain aneurysm is a cerebrovascular disorder in which weakness in the wall of a cerebral artery or vein causes a localized dilation or ballooning of the blood vessel.
A common location of cerebral aneurysms is on the arteries at the base of the brain, known as the Circle of Willis. Approximately 85% of cerebral aneurysms develop in the anterior part of the Circle of Willis, and involve the internal carotid arteries and their major branches that supply the anterior and middle sections of the brain. It is believed that aneurysms may result from congenital defects, preexisting conditions such as high blood pressure and atherosclerosis, or head trauma. Cerebral aneurysms occur more commonly in adults than in children but they may occur at any age.
Cerebral aneurysms are classified both by size and shape. Small aneurysms have a diameter of less than 15 mm. Larger aneurysms include those classified as large (15 to 25 mm), giant (25 to 50 mm), and super giant (over 50 mm). Saccular aneurysms are those with a saccular outpouching and are the most common form of cerebral aneurysm. Berry aneurysms are saccular aneurysms with necks or stems resembling a berry. Fusiform aneurysms are aneurysms without stems.
A small, unchanging aneurysm will produce no symptoms. Before a larger aneurysm ruptures, the individual may experience such symptoms as a sudden and unusually severe headache, nausea, vision impairment, vomiting, and loss of consciousness, or the individual may be asymptomatic, experiencing no symptoms at all. Onset is usually sudden and without warning. Rupture of a cerebral aneurysm is dangerous and usually results in bleeding into the meninges or the brain itself, leading to a subarachnoid hemorrhage (SAH) or intracranial hematoma (ICH), either of which constitutes a stroke. Rebleeding, hydrocephalus (the excessive accumulation of cerebrospinal fluid), vasospasm (spasm, or narrowing, of the blood vessels), or multiple aneurysms may also occur. The risk of rupture from an unruptured cerebral aneurysm varies according to the size of an aneurysm, with the risk rising as the aneurysm size increases. The overall rate of aneurysm rupture is estimated at 1.3% per year. The risk of short term re-rupture increases dramatically after an aneurysm has bled, though after approximately 6 weeks the risk returns to baseline.
Emergency treatment for individuals with a ruptured cerebral aneurysm generally includes restoring deteriorating respiration and reducing intracranial pressure. Currently there are two treatment options for brain aneurysms: surgical clipping or endovascular coiling. Either surgical clipping or endovascular coiling is usually performed within the first three days to occlude the ruptured aneurysm and reduce the risk of rebleeding.
The prognosis for a patient with a ruptured cerebral aneurysm depends on the extent and location of the aneurysm, the person's age, general health, and neurological condition. Some individuals with a ruptured cerebral aneurysm die from the initial bleeding. Other individuals with cerebral aneurysm recover with little or no neurological deficit. The most significant factors in determining outcome are severity of the aneurysm and age.
Abdominal aortic aneurysm (AAA) is a localized dilatation of the abdominal aorta, that exceeds the normal diameter by more than 50%. The normal diameter of the infrarenal aorta is 2 cm. It is caused by a degenerative process of the aortic wall. The aneurysm is most commonly located infrarenally (90%), other possible locations are suprarenal and pararenal. The aneurysm can extend to include one or both of the iliac arteries. An aortic aneurysm may also occur in the thorax.
AAA is uncommon in individuals of African, African American, Asian, and Hispanic heritage. The frequency varies strongly between males and females. The peak incidence is among males around 70 years of age, the prevalence among males over 60 years totals 2-6%. The frequency is much higher in smokers than in non-smokers (8:1). Other risk factors include hypertension and male sex. In the US, the incidence of AAA is 2-4% in the adult population. Rupture of the AAA occurs in 1-3% of men aged 65 or more, the mortality being 70-95%.
The exact causes of the degenerative process remain unclear. Known risk factors include genetic factors, hemodynamic influences, atherosclerosis, and various other factors such as infection, trauma, connective tissue disorders, arterities, etc. AAAs are commonly divided according to their size and symptomatology. An aneurysm is usually considered to be present if the measured outer aortic diameter is over 3 cm (normal diameter of aorta is around 2 cm). The natural history is of increasing diameter over time, followed eventually by the development of symptoms (usually rupture). If the outer diameter exceeds 5 cm, the aneurysm is considered to be large. For aneurysms under 5 cm, the risk of rupture is low, so that the risks of surgery usually outweigh the risk of rupture. Aneurysms less than 5 cm are therefore usually kept under surveillance until such time as they become large enough to warrant repair, or develop symptoms. The vast majority of aneurysms are asymptomatic. The risk of rupture is high in a symptomatic aneurysm, which is therefore considered an indication for surgery. Possible symptoms include low back pain, flank pain, abdominal pain, groin pain or pulsating abdominal mass. The complications include rupture, peripheral embolisation, acute aortic occlusion, aortocaval or aortoduodenal fistulae. On physical examination, a palpable abdominal mass can be noted. Bruits can be present in case of renal or visceral arterial stenosis.
The main treatment options for asymptomatic AAA are immediate repair and surveillance with a view to eventual repair. Surveillance is indicated in small aneurysms, where the risk of repair exceeds the risk of rupture. As an AAA grows in diameter the risk of rupture increases. Although some controversy exists around the world, most vascular surgeons would not consider repair until the aneurysm reached a diameter of 5 cm. The threshold for repair varies slightly from individual to individual, depending on the balance of risks and benefits when considering repair versus ongoing surveillance. The size of an individual's native aorta may influence this, along with the presence of comorbitities that increase operative risk or decrease life expectancy. Currently, the main modes of repair available for an AAA are open aneurysm repair (OR), and endovascular aneurysm repair (EVAR). Open repair is indicated in young patients as an elective procedure, or in growing or large, symptomatic or ruptured aneurysms. Open repair has been the mainstay of intervention from the 1950's until recently. Endovascular repair first became practical in the 1990's and although it is now an established alternative to open repair, its role is yet to be clearly defined. It is generally indicated in older, high-risk patients or patients unfit for open repair. However, endovascular repair is feasible for only a proportion of AAA's, depending on the morphology of the aneurysm. The main advantage over open repair is that the peri-operative period has less impact on the patient.
Stroke
Stroke is a group of diverse disorders encompassing several pathophysiological mechanisms. The clinical phenotype of stroke is complex but is broadly divided into: ischemic and hemorrhagic stroke. The majority of stroke events, appr 80%, is due to ischemia (cerebral infarction), that occurs when a cerebral artery becomes completely occluded and the blood supply to a part of the brain is totally or partially blocked (due to thrombosis or an embolism). Ischemic stroke is further subdivided into large artery disease (LAA) (also called large vessel disease, LVD), cardioembolic stroke and small vessel disease. Approximately 25% of ischemic stroke events are due to large-artery disease of the carotid and vertebral arteries, the two pairs of large arteries that supply the brain with blood. The most common cause of large-artery disease is atherosclerosis. Cardioembolic strokes are caused by an embolism that originates inside the heart. Embolism of cardiac origin accounts for about ¼ of ischemic strokes. Strokes due to cardioembolism are in general severe and prone to early and long-term recurrence. Ischemic heart disease, rheumatic mitral stenosis, and prosthetic cardiac valves are major sources of cardioembolic stroke but atrial fibrillation remains the commonest cause.
There is a continued and great need to understand the genetic variants conferring risk (increased and decreased) of the cardiovascular diseases. The present invention provides genetic variants that have been shown to be associated with susceptibility to cardiovascular disease, including MI, Coronary Artery Disease (CAD), Intracranial aneurysm (IA), Abdominal Aorta Aneurysm (AAA), Peripheral Arterial Disease (PAD) and Restenosis. These variants are useful in risk management and methods for therapeutic intervention of cardiovascular diseases.